Bisphosphonates, pharmaceutical compositions, and process for the treatment of irregularities in calcium metabolism

ABSTRACT

Novel bisphosphonates comprise compounds of the formula (I) ##STR1## wherein m and l are independently 1 or 2; R 1  represents hydrogen, a lower alkyl group, or an alkali metal cation; R 2  represents hydrogen, a lower alkyl group or an alkali metal cation; Y represents ═0 or ═N--OH, or --OH; and X represents --(CH 2 ) n  --, a branched alkylene group, or a branched or straight alkenylene or alkynylene chain optionally substituted by one or more oxygen or nitrogen atoms, wherein n is an integer from 3 to 24; with the provision that when l═m═1, Y is ═0, and R 1  and R 2  denote a lower alkyl group, n represents an integer from 9 to 20; and with the provision that when l═m═2, Y is --OH and R 1  and R 2  are methyl groups, n represents an integer from 9-24; and with the further provision that when l═m═2, Y is --OH and R 1  and R 2  are hydrogen, n represents 3, 5 or an integer from 7 to 24; or X is 
     
         --(CH.sub.2).sub.p --(OCH.sub.2 CH.sub.2).sub.q --O--(CH.sub.2).sub.p&#39; -- 
    
     wherein p and p&#39; are independently integers from 1 to 5 and q is an integer from 1 to 6; or X is 
     
         --(CH.sub.2).sub.t --O--(CH.sub.2).sub.s --O--(CH.sub.2).sub.t&#39; -- 
    
     wherein t and t&#39; are independently integers from 1 to 6 and s is an integer from 2 to 12; or X is 
     
         --B--A--B 
    
     wherein B represents a branched group or straight alkylene, or an alkenylene or alkynylene chain optionally substituted by one or more oxygen or nitrogen atoms, and A represents an aromatic group such as phenylene, naphthalenediyl, thiophenediyl or furandiyl.

This application is a division of application Ser. No. 07/570,266 filedAug. 20, 1990, now abandoned.

FIELD OF THE INVENTION

The present invention relates to novel bisphosphonates, processes fortheir preparation and pharmaceutical compositions containing the same.The compounds and the pharmaceutical compositions according to thepresent invention are suitable and useful for the treatment ofirregularities in calcium metabolism.

BACKGROUND OF THE INVENTION

There are several pathological conditions that involve irregularities incalcium metabolism. Such are some bone related diseases as Paget'sdisease, osteoporosis as well as osteolysis in bone metastases.

Bone metastases present a major problem in many frequently occurringmalignancies. Hypercalcemia, resulting from bone resorption, is a commonand very important complication of malignancy, causing most distressfulsymptoms, such as severe pain, spontaneous fractures, and may lead to ametabolic coma and death. Moreover, neoplastic cell-induced osteolysismay determine the localization and growth enhancement of the tumor. (G.R. Mundy, Bone, 8, supp. 1, S9-5 16 (1987); Calcium in BiologicalSystems, R. P. Rubin, G. B. Weiss, and J. W. Putney, Jr. eds. PlenumPress, N.Y. (1985)). Ectopic calcification is a seemingly opposite typeof pathological condition, characterized by the deposition for calciumphosphate in a number of clinically important diseases as, for example,atherosclerosis, kidney and renal calculus, arthritis, and bioprosteticheart valve calcification, and implanted biomaterial calcification suchas bioprostetic and prosthetic heart valves, vascular grafts, LVAD (leftventricular assist devices), contact lenses and a total artificialheart.

Bisphosphonates are a relatively new class of drugs that have beendeveloped for use in various metabolic diseases of bone, the targetbeing excessive bone resorption and inappropriate calcification andossification. (M. D. Francis and R. R. Martodam, in "The Role ofPhosphonates in Living Systems" R. L. Hilderbrand, ed. CRC Press, BocaRaton, Fla, 1983, pp. 55-96; H. Fleisch, Bone, 1987, 8, Supp. 1,S23-S28). Recently there have been reports of encouraging clinicaltrials utilizing bisphosphonates to treat hypercalcemia in patients withbreast cancer, myeloma, and bronchial carcinoma related osteolyticmetastases, in addition to the established usage of bisphosphonates inPaget's disease and for diagnostic purposes in bone mapping. However,bisphosphonate therapy is frequently accompanied by severe side effects.Bisphosphonates have been also found highly potent both in inhibitingbioprosthetic heart valve calcification, and in experimentalarteriosclerosis, however, this was accompanied by severe adverseeffects on bone development and overall somatic growth.

The currently used bisphosphonates all belong to the geminal type, inwhich the two phosphoryl groups are bound to the same carbon ("P-C-P"),and therefore may be viewed as pyrophosphate analogs in which the oxygenbetween the two phosphorus atoms is replaced by a carbon.

In contrast, monophosphonates, vicinal bisphosphonates (P-C-C-P) andcompounds in which the distance between the phosphoryl group is longer(P-(C)_(n) -P, n>2) are reported to be less active or inactive at all.

From the results obtained in various clinical studies using conventionalbisphosphonates it appears that there is a need for compounds which havegreater margin between the bone resorption inhibiting effect and thatinhibiting mineralization, without an increase in toxicity.

According to the present invention it was found that introduction ofmodifications into long chain bisphosphonates of type P-(C)_(n) -Pincreases the cation binding ability of these compounds, and inhibitsectopic calcification. The advantage in this type of compound ininteracting with calcium phosphate crystals is assumed to derive fromthe presence of an additional independent anchor site(s) in the moleculeas compared with known bisphosphonates. An additional advantage of thisnovel class of compounds is an effect of long duration and the enhancedability to interact with the cell membrane.

U.S. Pat.No. 3,012,054 from Mar. 18, 1960 and a paper by M. Kanaan andR. Burgada, Phosphorus and Sulfur, 1988, 37, 217-229, describe thepreparation of "tetraalkyl esters of diphosphonates" having thestructure: ##STR2## wherein R=alkyl radical containing 1-4 cabons andn=2 to 8, inclusive.

It should be emphasized that the patent mentioned deals only withtetraesters. It is well known that such dialkyl acylphosphonates, asmentioned, exhibit exteme instability toward water, and they hydrolyzeto the corresponding carboxylic acids both in acidic and alklineconditions. Consequently, hydrolysis of the tetraalkyl esters desoribedin the patent and the paper cited above would lead to dicarboxylic acidsHOOC--(CH₂)_(n) --COOH. Therefore, the syntheses of dealkylatedderivatives such as represented by the formulas below: ##STR3## requirespecial nonhydrolytic methods, and by no means are the dealkylatedcompounds obvious derivatives of the teraesters.

Neither esters nor acids of bisphosphonates in which the twoketophosphonic groups such as aromatic rings etc., have been reported.

SUMMARY OF THE INVENTION

The present invention relates to novel bisphosphonates of the formula(I) ##STR4## wherein m and l are independently 1 or 2; R₁ representshydrogen, a lower alkyl group, or an alkali metal cation; R₂ representshydrogen, a lower alkyl group or an alkali metal cation; Y represents ═0or ═N--OH, or --OH; and X represents --(CH₂)_(n) --, a branched alkylenegroup, or a branched or straight alkenylene or alkynylene chainoptionally substituted by one or more oxygen or nitrogen atoms, whereinn is an integer from 3 to 24; with the provision that when l=m=l, Y is=0, and R₁ and R₂ denote a lower alkyl group, n represents an integerfrom 9 to 20; and with the provision that when l=m=2, Y is --OH and R₁and R₂ are methyl groups, n represents an integer from 9-24; and withthe further provision that when l=m=2, Y is --OH and R₁ and R₂ arehydrogen, n represents 3, 5 or an integer from 7 to 24; or X is

    --(CH.sub.2).sub.p --(OCH.sub.2 CH.sub.2).sub.q --O--(CH.sub.2).sub.p' --

wherein p and p' are independently integers from 1 to 5 and q is aninteger from 1 to 6; or X is

    --(CH.sub.2).sub.t --O--(CH.sub.2).sub.s --O--(CH.sub.2).sub.t' --

wherein t and t' are independently integers from 1 to 6 and s is aninteger from 2 to 12; or X is

    -B-A-B

wherein represents a branched group or straight alkylene, or analkenylene or alkynylene chain optionally substituted by one or moreoxygen or nitrogen atoms, and A represents an aromatic group such asphenylene, naphthalenediyl, thiophenediyl or furandiyl.

Preferably R₁ is hydrogen or a methyl group, R₂ is a methyl group, or asodium or lithium cation, Y is ═0 or ═NOH, B is a --CH₂ -- group and Ais phenylene, optionally substituted.

The present invention further relates to a process for obtaining theabovementioned compounds according to formula (I) and pharmaceuticalcompositions containing the same.

DETAILED DESCRIPTION

The process for the preparation of tetraalkyl α,α'-diketobisphosphonates comprises adding trimethyl phosphite to thecorresponding dicarboxylic acid dihalide.

The process for obtaining dialkyl αα'-diketobisphosphonates disaltscomprises adding tetraalkyl diketobisphosphonates dissolved in acetoneor acetonitrile to a solution of sodium iodide or lithium bromide inacetonitrile.

The process for the preparation of hydrogen α,α'-diketobisphosphonatedisalts (sodium) comprises dissolving tetraalkyl diketobisphosphonate indry nonhydroxylic solvent and addition of bromotrimethylsilane.

The process for the synthesis of dialkylα,α'-bishyroxyiminobisphosphonate disalts comprises suspending dimethyldilithium α,α'-bishydroxyiminobisphosphonate, in absolute ethanol, andin a separate flask dissolving sodium in absolute ethanol. The resultingsolution is added slowly to hydroxylamine hydrochloride in methanol.

The process for the synthesis of octa-alkyl αw' dihydroxy αα wwtetrakisphosphonates is by adding αw diacyldihalide to a mixture oftrialkyl phosphite and dialkyl phosphite.

The process for the synthesis of αw dihydroxy αα ww tetrakisphosphonicacid consists of adding hydrochloric acid to the octaalkyl esters.

The present invention also relates to pharmaceutical compositions whichcomprise a compound according to the invention as active ingredient andsuitable carriers optionally suitable for controlled release deliverysystems and/or other additives.

The drug delivery systems may include any conventional suitable carrieror controlled release system (sustained release, delayed actionpreparations), based on a polymeric vehicle (e.g. silicon, polyurethane,or any other biocompatible polymer), or based on degradable systems(e.g. chitosan, collagen, or any other degradable/biodegradablecarrier).

Chitosan is soluble only in acidic pH, preferably by acetic acid. Drugdelivery systems based on chitosan as a carrier can be prepared in aconventional and in an innovative way. In the first method the drug isdissolved with the polymer in acidic pH (preferably, 1 to 10% w/w solidswith acetic acid) and the solvent is evaporated or extracted by anon-solvent. By this method sustained release drug delivery systems inthe form of film (matrix), micromatrics, microcapsules or microspherescould be prepared.

An innovative method of preparing chitosan-based drug delivery system isbased on the alkalinity of chitosan (amino functional groups) and theacidity of phosphonates (as free acid obtained from the sodium salt by acatonic exchange resin). The drug in its acid form is reacted withchitosan yielding a soluble chitosan-phosphonate salt without therequirement for another exterior acid, followed by waterevaporation/extraction as above. By this method the controlled releaseof the drug is governed not only by the matrix but also by thedissociation of the carrier-drug salt. Additional advantage is thepossible targeting of the drug by chitosan. The chitosan-phosphonatesalt could be embedded in chitosan for further delay of drug release.

The treatment with the controlled release delivery system is utilized bysubdermal implantation (as was done in FIG. 1) or by site specificimplantation, with the aim being optimization of therapy, using lowerdosage, minimizing systemic side effects, and effective prolongedtreatment with better patient compliance.

The novel bisphosphonates, according to the present invention, preventcalcium precipitation from metastable calcium and phosphate solution.Profound inhibition of rat, subdermal bioprosthetic heart valve tissuecalcification was achieved, by coimplantion of Alzet osmotic pumpsreleasing the drug, and tissue cusps. Therapy was achieved without sideeffects, as exhibited by the normal somatic growth. These in-vivoresults are summarized in FIG. 1.

The novel bisphosphonates, according to the present invention are usefulin the treatment of the following diseases: Osteoporosis (includingdisuse and postmenopausal osteoporosis), Hypercalcemia of Malignancy,(Direct) anticancer effect, Heterotopic Ossification (Hip Arthroplasty,Spinal cord injury, Myositis ossificans), Paget's disease,Hyperphosphatemia (e.g. Diabetes).

It can be seen that said compounds are useful not only for directtreatment of various diseases but also for treatment of the symptoms ofthe diseases (e.g. Hyperphosphatemia or Hypercalcemia).

The compounds according to the present invention are also useful asdiagnostics (e.g. Nuclear Medicine).

The compounds according to the present invention may possess alsoindustrial applications which are listed below (R. L. Hilderbrand, TheRole of Phosphonates in Living Systems, Chapter 7, page 172, CRC Press);Adhesives; Agents for extraction, concentration, and purification ofuranium, thorium, and plutonium; Antioxidants; Antistatic agents;Blowing agents; Catalysts; Corrosion inhibitors; Coupling agents;Crystallization inhibitors; Dentifrice compositions; Deodorants;Detergent additives; Detergents for cleaning metal surfaces; Dyemodifiers; Flame retardant polymers; Flame retardants for textiles; Fireretardants for synthetic fibers; Flotation agents; Fuel additives;Gelling agents; Hardening oil composites; Heat and light stabilizers;Hydraulic fluid additives; Ion exchange resins; Lubricants; Photography;Plasticizers; Polyester, polyethylene, and polycarbonate discolorationinhibitors; Polyurethane additives; Rayon additives; Resin and plasticadditives; Scale inhibitors; Settling retardants; Sequestering agents;Solvent extraction; Suspending agents; Synthetic fiber preparation;Viscosity modifiers; Wood fireproofing agents.

The invention is further illustrated by means of the followingnon-limiting examples.

EXAMPLES

General method for the synthesis of tetraelkylα,α'-diketobisphosphonates. Trimethyl phosphite (0.4 mole) was addeddropwise to the dicarboxylic acid dichloride (0.2 mole) at 5° C. Afterthe addition was completed, the reaction mixture was stirred for 1 hr atambient temperature.

Tetramethyl adipoylbisphosphonate was obtained in a yield of 90%. IR(neat) 1697s, 1260s, 1030s cm⁻¹. NMR; (CDCl₃) ¹ H: δ 3.87 (12H, J=10.64Hz), 2.85 (4H, m), 1.65 (4H, m).

Tetramethyl suberoylbisphosphonate was obtained in a yield of 90%. IRspctrum (neat) 1696s, 1265s, 1034s cm⁻¹. NMR (CDCl₃); ¹ H: δ 3.87 (12H,d, J=10 Hz), 2.82 4H, t, J=7.2 Hz), 1.63 (4H, m), 1.32 (4H, m), ³¹ P:δ=0.88 (sept). These compounds decomposed upon attempted distillation,but they were sufficiently pure to be used for the next step in thesynthesis without further purification.

Synthesis of Me₂ O₃ P--CO--(CH₂)₁₀ --CO--PO₃ Me₂

Tetramethyl dodecanedioldiphosphonate. 8.03 g (0.03 mol) ofdodecanedicyl dichloride was added, drop by drop, with stirring to asolution of 7.82 g (0.0636 mol) trimethyl phosphite in dry toluene at-10 C. under a nitrogen atmosphere. The reaction mixture was stirred atroom temperature for about 24 h. The toluene and the excess trimethylphosphite were evaporated at reduced pressure to yield an oily product.In the ³¹ P nmr spectrum the product showed a septet at the chemicalshift of δ -4.4 ppm.

General method for the synthesis of dialkyl α,α'-diketobisphosphonatedisalts. Tetraalkyl diketobisphosphonate (0.5 mole) was dissolved in 50ml dry acetone or acetonitrile, and the solution was added to a solutionof sodium iodide (1.1 mole) in dry acetone (30 ml) or lithium bromide inacetonitrile. The reaction mixture was stirred overnight at roomtemperature. The precipitate was filtered, washed with dry acetone oracetonitrile and dried. The yields are>85%.

Dimethyl dilithium adipoylbisphosphonates, yield was 95%, m.p.>250° C.,IR (nujol): 1660s, 1210s, 1110s, 1020s cm⁻¹. NMR (D₂ O) ¹ H: δ 3.6 (6H,d, J=10.67 Hz), 2.85 (4H, m), 1.6 (4H, m).

Dimethyl dilithium suberoylbisphosphonate, yield 100%, m.p.>250° C., IR(nujol): 1670s, 1216s, 1110s, 1040s cm⁻¹.NMR (D₂ O) ¹ H δ 3.65 (6H, d,J=10.56 Hz), 2.87 (4H, t, J=7.2 Hz), 1.64 (4H, m) 1.36 (4H, m).

General method for the synthesis of dihydrogen α,α'-diketobisphosphonatedisalts (sodium). 0.01 mole of tetramethyl diketobisphosphonate wasdissolved in dry acetonitrile (20 ml). 0.066 mole (9 ml) ofbromotrimethylsilane was added slowly and the reaction mixture wasstirred at ambient temperature for three hours. The acetonitrile wasevaporated in vacuum (keeping the temperature below 30° C.). A solutionof sodium hydroxide (0.02 Mole) in methanol (25 ml) was added to theresidue and the reaction mixture was stirred overnight at the ambienttemperature. The white precipitate was filtered, washed with methanol(15 ml) and dried.

Disodium dihydrogen adipoylbisphosphonate, yield 90%, m.p.>250° C., IRKBr 1675s, 1191s, 1055s cm⁻¹. NMR (D₂ O) ¹ H: δ 2.88 (4H, m), 1.6 (4H,m). ³¹ P: δ=-2.98, -3.44 s. Anal.: Calcd.: C, 22.64; H, 3.14. Found: C,22.41; H, 3.2.

Disodium dihydrogen suberoylbisphosphonate, yield 90%, m.p.>250°. IR(KBr) 1677s, 1214s, 1110s, 1075s cm⁻¹. NMR (D₂ O) ¹ H: δ 2.8 (4H, t,J=7.2 Hz), 1.58 (4H, m), 1.31 (4H, m), ³¹ P: δ=-3.23, 3.7s. Anal.:Calcd. C, 27.75; H, 4.05, Found, C, 26.93; H, 3.92.

Disodium dihydrogen terephthaloylbisphosphonate, yield 90%, m.p.>250°C., IR: 1641, 1682 cm⁻¹.

Disodium dihydrogen isophthaloylbisphosphonate, yield 90%, m.p.>250° C.,IR: 1641 cm⁻¹.

Synthesis of MHO₃ P--CO--(CH₂)₁₀ --CO--PO₃ HM (M=Cation, e.g. Na⁺, Li⁺,etc.)

Dihydrogen disodium dodecanedioylphosphonate. Tetramethyldodecanedioyldiphosphonate obtained in the previous step was dissolvedin dry benzene (30 ml) and cooled to 0° C. 30.2 g (0.198 mole) ofbromotrimethylsilane was added slowly to the solution and the reactionmixture was stirred at the ambient temperature for one hour. Thereaction mixture was evaporated in vacum (keeping the temperature below30°) and a solition of sodium hydroxide 2.4 g (0.06 mol) in methanol (70ml) was added with stirring to the residue and the reaction mixture wasstirred for 2 hrs. at ambient temperature and the white precipitate wasfiltered, washed with methanol (15 ml) and dried. In the ⁻ P nmrspectrum the product showed a singlet at δ-0.2 ppm. ¹ H nmr spectrum δ2.50 ppm (4H, t), 1.24 ppm (4H, m), 0.99 ppm (12H, broad singlet).

Synthesis of dialkyl α,α'-bishydroxyiminobisphosphonate disalts. 0.01mole of dimethyl dilithium α,α'-bishydroxyiminobisphosphonate wassuspended in absolute ethanol (10 ml), in flask A. In a separate flask0.03 mol sodium was dissolved in absolute ethanol (10 ml), in an icebath under a reflux condenser, equipped with a calcium chloride tube.The resulting solution was added slowly to a solution of 0.03 molhydroxylamine hydrochloride in methanol (15 ml), until the solution wasneutral to pH paper. After stirring for 5 minutes in an ice bath, sodiumchloride was filtered, washed with ethanol and the filtrate was added tothe solution of dimethyl dilithium salt in flask A. The reaction mixturewas left to stir for 1-2 days at the ambient temperature, it wasfiltered, washed successively with acetonitrile and ether and dried invacuo at room temperature.

Dimethyl dilithium 1,6-bishydroxyiminohexmethylene-1,6-bisphosphonatewas obtained in a yield of 90%, m.p.>250° C., IR (KBr): 1650w,b, 1221s,1085s, 1049s cm⁻¹. NMR (D₂ O) ¹ H: δ 3.55 (6H, d, J=10.8 Hz), 2.5 (4H,m), 1.62 (4H, m).

Dimethyl dilithium 1,8-bishydroxyiminooctamethylene-1,8-bisphosphonateyield 90%, m.p.>250° C., IR (KBr): 1665w,b, 1227s, 1087s, 1050s, cm⁻¹.NMR (D₂ O): ¹ H δ 3.56 (6H, d, J=10.89 Hz), 2.5 (4H, m), 1.6 (4H, m),1.4 (4H, m). ##STR5##

Octamethy 1,12-dihydroxydodecane-1,1,12,12-tetrakisphosphonate

5.34 g (0.02 mol) 1,12-dodecanedioyl dichloride was added dropwise, withstirring, in a nitrogen atmosphere, to a mixture of 4.96 g (0.04 mol) oftrimethyl phosphite and 4.40 g (0.04 mol) of dimethyl phosphite at roomtemperature. The mixture was stirred for 10 hrs at 90° C. and thereaction mixture was evaporated under reduced pressure. The oily residue(9.8 g) showed a broad signal at δ=22.3 ppm in the ³¹ P nmr spectrum.

1.12-Dihydroxydodecane-1,1,12,12-tetrakisphosphonic acid tetrasodiumsalt. ##STR6## The product obtained in the previous step was dissolvedin concentrated (32%) hydrochloric acid and refluxed for 72 hrs. Thesolution was cooled and filtered to remove impurities, the excess acidwas evaporated, the residue dissolved in warm distilled water andconcentrated solution of sodium hydroxide was added dropwise, to pH 4when the product started to precipitate. The precipitate which wascollected by filtration, showed in the ³¹ p nmr spectrum a triplet atδ=19.58 ppm (J=14 Hz).

In vitro test:

A novel bisphosphonate according to the present invention was added to amixture of calcium chloride and sodium phosphate. After a period of timethe calcium and phosphous concentration in the filrate was determined.

FIG. 2 shows that adipoylbisphosphonate (C4 diacid) ##STR7## preventsthe precipitation of calcium and phosphorus in the solution highlyeffectively while the C10 analog is only slightly effective.

The tetrakisphosphonate is also highly effective. The above novelphosphonates were compared to two commercial compounds ##STR8##

In vivo test:

FIG. 3 shows in vivo anticalcification effect of novel bisphosphonates.

The novel bisphosphonates were: ##STR9## They were compared to thecommercial compounds:

We claim:
 1. Bisphosphonate compounds of the formulawherein n=an integerfrom 3 to 24 R=hydrogen or a monovalent alkali metal cation.
 2. Acompound according to claim 1 having the formula ##STR11##
 3. A compoundaccording to claim 1 having the formula ##STR12##
 4. A compoundaccording to claim 1 having the formula ##STR13##
 5. Pharmaceuticalcomposition which comprises a compound according to claim 3 as an activeingredient, and a pharmaceutically acceptable carrier.
 6. Pharmaceuticalcomposition according to claim 5, wherein the carrier is suitable for acontrolled release delivery system.
 7. Pharmaceutical compositionaccording to claim 6 wherein the carrier is based on a polymericvehicle.
 8. Pharmaceutical composition according to claim 7, whereinsaid polymeric vehicle is based on silicon, polyurethane, or anotherbiocompatible polymer.
 9. Pharmaceutical composition according to claim6, wherein the carrier is based on a degradable system. 10.Pharmaceutical composition according to claim 9, wherein said degradablecarrier is based on chitosan, collagen or another biodegradable carrier.11. Pharmaceutical composition according to claim 6, wherein thecontrolled release delivery system is adapted for subdermalimplantation.
 12. Pharmaceutical composition according to claim 6,wherein the controlled release delivery system is adapted for sitespecific implantation.
 13. A method for the treatment of osteoporosishypercalcemia of malignancy; heterotopic ossification Paget's disease;or hyperphosphatemia comprising administration of a pharmaceuticalcomposition as defined by claim
 5. 14. A pharmaceutical compositioncomprising an effective amount of a compound according to claim 3 and apharmaceutically acceptable excipient or carrier.
 15. A method fortreating irregularities in calcium metabolism or the symptoms associatedtherewith comprising administering to a host an effective amount of acompound according to claim
 3. 16. Bisphosphonate compounds of theformula ##STR14## wherein n=an integer from 3 to 24R₁ =a lower alkylgroup, and R₂ =hydrogen or a monovalent alkali metal cation.
 17. Acompound according to claim 16 having the formula ##STR15##
 18. Thecompound according to claim 16 having the formula ##STR16##
 19. Apharmaceutical composition comprising an effective amount of a compoundaccording to claim 16 and a pharmaceutically acceptable excipient orcarrier.
 20. A method for treating irregularities in calcium metabolismor the symptoms associated therewith comprising administering to a hostan effective amount of a compound according to claim 16.